Celiac disease (CD) is a major public health problem affecting at least 1% of the general population and leading to significant morbidity and mortality. Despite tremendous progress in the past decade, CD is still under-diagnosed due to low awareness and lack of a comprehensive screening program. Applications of highly sensitive and specific serological markers such as autoantibodies to tissue transglutaminase (tTG) suggest that up to 4% of the general population may have CD. The natural history of CD is only partially understood and the boundaries between clinical and subclinical disease remain blurred. While early detection and treatment with gluten-free diet (GFD) seems logical, the evidence is lacking to inform optimal timing, intensity and duration of gluten exclusion. Our unique large prospective study of children at high-risk of CD (R01 DK50979, 9/1995-4/2011, M. Rewers, P.I.) has answered some of the key research priorities identified by expert committees. In this competing renewal application we are proposing to address additional unanswered challenges facing celiac research today: Specific Aim 1. Determine the cumulative incidence, genetic, and environmental predictors of persistent tTG and CD by age 15 years. We will accomplish this goal through continuing follow-up for development of tTG and CD of already established cohorts: A) General population children with high risk HLA-DQ genotypes (n=1,268; current median age 10.8 yr); B) Non-diabetic first degree relatives of patients with type 1 diabetes (n=1,082; current median age 13.6 yr); C) Children with type 1 diabetes (T1D) (n=4,677); During the proposed 5-year follow-up, 66% of the study participants in cohorts A and B will achieve 15 yrs of age and all will be at least 10. This will allow for a comprehensive assessment of the natural history of CD throughout childhood and adolescence. Our preliminary data suggest that more than 60% childhood CD cases in the U.S. develop after age 5. It is likely that the genetic and environmental causes of CD manifesting in older children differ from those in pre-school children. Future screening programs need to take this into account. Specific Aim 2. Define predictors of clinically relevant outcomes: growth, micronutrient deficiencies, bone mineralization and quality of life in a large prospective followed cohort of children with screening-identified tTG+ and appropriate controls. Specific Aim 3. Map out the evolution of humoral response to wheat gliadins and selected glutenins, hordeins and secalins from early childhood to adulthood.